HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XCOPRI

safely and effectively. See full prescribing information for XCOPRI.

XCOPRI® (cenobamate tablets), for oral use, CV

Initial U.S. Approval: 2020

__________________

INDICATIONS AND USAGE _________________

XCOPRI is indicated for the treatment of partial-onset seizures in adult patients.

(1) _______________

DOSAGE AND ADMINISTRATION ______________

• Swallow tablets whole. Do not crush or chew. (2.1)

• The recommended initial dosage of XCOPRI is 12.5 mg once daily,

titrated to the recommended maintenance dosage of 200 mg once daily. The recommended titration schedule should not be exceeded. The

maximum dosage is 400 mg once daily. (2.2)

• Hepatic impairment: For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 200 mg once daily. (2.3, 8.7, 12.3)

______________ DOSAGE FORMS AND STRENGTHS

_____________

• Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg. (3)

___________________ CONTRAINDICATIONS

___________________

• Hypersensitivity to cenobamate or any of the inactive ingredients in

XCOPRI. (4)

• Familial Short QT syndrome. (4) _______________

WARNINGS AND PRECAUTIONS ______________

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/

Multi-Organ Hypersensitivity: Discontinue if no alternate etiology. (5.1)

• QT Shortening: Use caution when administering XCOPRI with other drugs that shorten the QT interval (5.2)

• Suicidal Behavior and Ideation: Monitor patients for suicidal behavior

and ideation. (5.3) • Neurological Adverse Reactions: Monitor for somnolence and fatigue and

advise patients not to drive or operate machinery until they have gained

sufficient experience on XCOPRI. Concomitant use with other CNS depressants or alcohol may have additive effects. (5.4)

• Withdrawal of Antiepileptic Drugs: XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency. (5.5)

___________________ ADVERSE REACTIONS

___________________

The most common adverse reactions in patients receiving XCOPRI (at least

10% for XCOPRI and more frequently than placebo) include somnolence, dizziness, fatigue, diplopia, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact SK Life

Science, Inc. at 1-866-657-5574 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch. ___________________

DRUG INTERACTIONS____________________

• Phenytoin: Gradually decrease phenytoin dosage by up to 50% (7.1)

• Phenobarbital and Clobazam: Reduce dosage as needed when used

concomitantly with XCOPRI. (7.1) • Lamotrigine, Carbamazepine: Increase dosage as needed when used

concomitantly with XCOPRI. (7.1)

• CYP2B6 and CYP3A Substrates: Increase dosage as needed when used concomitantly with XCOPRI. (7.1)

• CYP2C19 Substrates: Reduce dosage as needed when used concomitantly

with XCOPRI. (7.1) • Oral Contraceptives: Effectiveness of hormonal oral contraceptives may

be reduced when administered concomitantly with XCOPRI. Women

should use additional or alternative non-hormonal birth control. (7.1) ______________

USE IN SPECIFIC POPULATIONS _______________

• Pregnancy: Based on animal data, may cause fetal harm. (8.1)

• Renal Impairment: Use with caution and dosage reduction may be considered in patients with mild to moderate (CLcr 30 to < 90 mL/min)

and severe (CLcr < 30 mL/min) renal impairment. Use not recommended

in end-stage renal disease (CLcr < 15 mL/min) undergoing dialysis. (8.6)

• Hepatic Impairment: Use with caution in patients with mild to moderate

hepatic impairment; lower maximum dosage and additional dosage

reduction may be considered. Use of XCOPRI in patients with severe hepatic impairment is not recommended. (2.3, 8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide.

Revised: 4/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

2.2 General Dosing Recommendations

2.3 Dosage Modifications in Patients with Hepatic Impairment 2.4 Discontinuation of XCOPRI

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS)/Multiorgan Hypersensitivity 5.2 QT Shortening

5.3 Suicidal Behavior and Ideation

5.4 Neurological Adverse Reactions 5.5 Withdrawal of Antiepileptic Drugs

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience 7 DRUG INTERACTIONS

7.1 Effect of XCOPRI on Other Drugs

7.2 Drugs that Shorten the QT Interval 7.3 CNS Depressants and Alcohol

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use 8.5 Geriatric Use

8.6 Patients with Renal Impairment

8.7 Patients with Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse 9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied 16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

XCOPRI is indicated for the treatment of partial-onset seizures in adult patients.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

XCOPRI may be taken any time with or without food. Swallow tablets whole with liquid. Do not

crush or chew.

2.2 General Dosing Recommendations

Monotherapy and Adjunctive Therapy

XCOPRI is administered orally once daily. The recommended dosage and titration, which should

not be exceeded because of the potential for serious adverse reactions [see Warnings and

Precautions (5.2)], is included in Table 1.

Table 1: Recommended Dosage for Partial-Onset Seizures in Adults

Initial Dosage

Week 1 and 2 12.5 mg once daily

Titration Regimen

Week 3 and 4 25 mg once daily

Week 5 and 6 50 mg once daily

Week 7 and 8 100 mg once daily

Week 9 and 10 150 mg once daily

Maintenance Dosage

Week 11 and thereafter 200 mg once daily

Maximum Dosage

If needed based on clinical response and

tolerability, dose may be increased above 200 mg

by increments of 50 mg once daily every two

weeks to 400 mg.

400 mg once daily

2.3 Dosage Modifications in Patients with Hepatic Impairment

For patients with mild to moderate (5-9 points on Child-Pugh assessment) hepatic impairment, the

maximum recommended dosage is 200 mg once daily [see Use in Specific Populations (8.7)].

XCOPRI is not recommended for use in patients with severe hepatic impairment [see Clinical

Pharmacology (12.3)].

2.4 Discontinuation of XCOPRI

If XCOPRI is discontinued, the dosage should be gradually reduced over a period of at least 2

weeks, unless safety concerns require abrupt withdrawal [see Warnings and Precautions (5.1,

5.5)].

3 DOSAGE FORMS AND STRENGTHS

XCOPRI tablets are available in the following strengths, shapes, colors, and tablet markings (Table

2).

Table 2: XCOPRI Tablet Presentations

Tablet Strength Tablet Color/Shape Tablet Markings

12.5 mg Uncoated round white to off-white tablets SK on one side and 12 on the other side

25 mg Film coated round brown tablets SK on one side and 25 on the other side

50 mg Film coated round yellow tablets SK on one side and 50 on the other side

100 mg Film coated round brown tablets SK on one side and 100 on the other side

150 mg Film coated round light orange tablets SK on one side and 150 on the other side

200 mg Film coated modified oval light orange

tablets

SK on one side and 200 on the other side

4 CONTRAINDICATIONS

XCOPRI is contraindicated in patients with:

• Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI [see

Warnings and Precautions (5.1) and Description (11)]

• Familial Short QT syndrome [see Warnings and Precautions (5.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS)/Multiorgan Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan

hypersensitivity, has been reported in patients taking XCOPRI. DRESS has occurred, including

one fatality, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS

were reported in an open-label safety study of 1339 partial-onset seizure patients when XCOPRI

was initiated at 12.5 mg once daily and titrated every two weeks. This finding does not establish

that the risk of DRESS is prevented by a slower titration; however, XCOPRI should be initiated at

12.5 mg once daily and titrated every two weeks [see Dosage and Administration (2.2)]. DRESS

typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial

swelling, in association with other organ system involvement, such as hepatitis, nephritis,

hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral

infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ

systems not noted here may be involved. It is important to note that early manifestations of

hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not

evident. If such signs or symptoms are present, the patient should be evaluated immediately.

XCOPRI should be discontinued immediately and not restarted if an alternative etiology for the

signs or symptoms cannot be established [see Contraindications (4)].

5.2 QT Shortening

In a placebo-controlled study of the QT interval, a higher percentage of subjects who took XCOPRI

(31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to

placebo (6-17%). Reductions of the QTc interval below 300 msec were not observed [see Clinical

Pharmacology (12.2)]. Familial Short QT syndrome is associated with an increased risk of sudden

death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this

syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec.

Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients

with Familial Short QT syndrome should not be treated with XCOPRI [see Contraindications (4)].

Caution should be used when administering XCOPRI and other drugs that shorten the QT interval

as there may be a synergistic effect on the QT interval that would increase the QT shortening risk.

5.3 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior

in patients taking these drugs for any indication. Patients treated with any AED for any indication

should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior,

and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of

11 different AEDs showed that patients randomized to one of the AEDs had approximately twice

the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to

patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks,

the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients

was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase

of approximately one case of suicidal thinking or behavior for every 530 patients treated. There

were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but

the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week

after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal

thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data

analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a

range of indications suggests that the risk applies to all AEDs used for any indication. The risk did

not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in

the Pooled Analysis

Indication Placebo Patients

with Events Per

1000 Patients

Drug Patients

with Events Per

1000 Patients

Relative Risk:

Incidence of

Events in Drug

Patients/Incidence

in Placebo

Patients

Risk Differences:

Additional Drug

Patients with

Events Per 1000

Patients

Epilepsy 1.0 3.4 3.5 2.4

Psychiatric 5.7 8.5 1.5 2.9

Other 1.0 1.8 1.9 0.9

Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with

epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk

differences were similar for epilepsy and psychiatric indications.

Anyone considering prescribing XCOPRI or any other AED must balance this risk with the risk

of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are

themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and

behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to

consider whether the emergence of these symptoms in any given patient may be related to the

illness being treated.

5.4 Neurological Adverse Reactions

Somnolence and Fatigue

XCOPRI causes dose-dependent increases in somnolence and fatigue-related adverse reactions

(somnolence, fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) [see Adverse

Reactions (6.1)]. In Study 1 and Study 2, 31% of patients randomized to receive XCOPRI at 100

mg/day, 36% of patients randomized to receive XCOPRI at 200 mg/day, and 57% of patients

randomized to receive XCOPRI at 400 mg/day reported at least one of these adverse reactions,

compared to 19% of patients who received placebo. Somnolence and fatigue-related adverse

reactions were serious in 0.4% of XCOPRI-treated patients compared to no patients who received

placebo and led to discontinuation in 2% of XCOPRI-treated patients compared to 1% of patients

who received placebo.

Dizziness and Disturbance in Gait and Coordination

XCOPRI causes dose-dependent adverse reactions related to dizziness and disturbance in gait and

coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and

abnormal coordination) [see Adverse Reactions (6.1)]. In Study 1 and Study 2, 21% of patients

randomized to receive XCOPRI at 100 mg/day, 31% of patients randomized to receive XCOPRI

at 200 mg/day, and 52% of patients randomized to receive XCOPRI at 400 mg/day reported at

least one of these adverse reactions, compared to 18% of patients who received placebo. Dizziness

and disturbance in gait and coordination adverse reactions were serious in 2% of XCOPRI-treated

patients compared to no patients who received placebo and led to discontinuation in 5% of

XCOPRI-treated patients compared to 1% of patients who received placebo.

Cognitive Dysfunction

XCOPRI causes adverse reactions related to cognitive dysfunction related-events (i.e., memory

impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder,

slowness of thought, disorientation, and psychomotor retardation) [see Adverse Reactions (6.1)].

In Study 1 and Study 2, 6% of patients randomized to receive XCOPRI at 100 mg/day, 6% of

patients randomized to receive XCOPRI at 200 mg/day, and 9% of patients randomized to receive

XCOPRI at 400 mg/day reported at least one of these adverse reactions, compared to 2% of

patients who received placebo. No cognitive dysfunction-related events were serious in XCOPRI-

treated patients or in patients who received placebo. Cognitive dysfunction related adverse

reactions led to discontinuation in 0.4% of XCOPRI-treated patients compared to no patients who

received placebo.

Visual Changes

XCOPRI causes adverse reactions related to visual changes including diplopia, blurred vision, and

impaired vision [see Adverse Reactions (6.1)]. In Study 1 and Study 2, 9% of patients randomized

to receive XCOPRI at 100 mg/day, 9% of patients randomized to receive XCOPRI at 200 mg/day,

and 18% of patients randomized to receive XCOPRI at 400 mg/day reported at least one of these

adverse reactions, compared to 2% of patients who received placebo. No visual change-related

events were serious in XCOPRI-treated patients or in patients who received placebo. Visual

change led to discontinuation in 0.5% of XCOPRI-treated patients compared to no patients who

received placebo.

Risk Amelioration

Prescribers should advise patients against engaging in hazardous activities requiring mental

alertness, such as operating motor vehicles or dangerous machinery, until the effect of XCOPRI is

known. Patients should be carefully observed for signs of central nervous system (CNS)

depression, such as somnolence and sedation, when XCOPRI is used with other drugs with

sedative properties because of potential additive effects.

5.5 Withdrawal of Antiepileptic Drugs

As with most antiepileptic drugs, XCOPRI should generally be withdrawn gradually because of

the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.4)

and Clinical Studies (14)]. But if withdrawal is needed because of a serious adverse event, rapid

discontinuation can be considered.

6 ADVERSE REACTIONS

The following serious adverse reactions are described in more detail in the Warnings and

Precautions section of the labeling:

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

Hypersensitivity [see Warnings and Precautions (5.1)]

• QT Shortening [see Warnings and Precautions (5.2)]

• Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)]

• Neurological Adverse Reactions [see Warnings and Precautions (5.4)]

• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and for varying durations,

adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared

with frequencies in the clinical trials of another drug and may not reflect the frequencies observed

in practice.

In all controlled and uncontrolled trials performed in adult partial-onset seizure patients, XCOPRI

was administered as adjunctive therapy to 1944 patients. Of these patients, 1575 were treated for

at least 6 months, 710 for at least 12 months, 349 for at least 24 months, and 320 for at least 36

months. A total of 658 patients (442 patients treated with XCOPRI and 216 patients treated with

placebo) constituted the safety population in the pooled analysis of placebo-controlled studies in

patients with partial-onset seizures (Studies 1 and 2) [see Clinical Studies (14)]. The adverse

reactions presented in Table 4 are based on this safety population; the median length of treatment

in these studies was 18 weeks. Of the patients in those studies, approximately 49% were male,

76% were Caucasian, and the mean age was 39 years.

In Study 1 and Study 2, adverse events occurred in 77% of patients treated with XCOPRI and 68%

treated with placebo. Table 4 gives the incidence of adverse reactions that occurred in subjects

with partial-onset seizures in any XCOPRI treatment group and for which the incidence was

greater than placebo during the controlled clinical trials. The most common adverse reactions that

occurred in XCOPRI-treated patients (incidence at least 10% and greater than placebo) were

somnolence, dizziness, fatigue, diplopia, and headache.

The discontinuation rates because of adverse events were 11%, 9%, and 21% for patients

randomized to receive XCOPRI at doses of 100 mg/day, 200 mg/day, and 400 mg/day,

respectively, compared to 4% in patients randomized to receive placebo. The adverse reactions

most commonly (1% or greater in any XCOPRI treatment group, and greater than placebo) leading

to discontinuation, in descending order of frequency, were ataxia, dizziness, somnolence, diplopia,

nystagmus, and vertigo.

Table 4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in

Patients with Partial-Onset Seizures with XCOPRI Frequency in Any Treatment

Arm Greater Than 1% Over Placebo

XCOPRI Placebo

100mg 200mg 400mg

Adverse Reaction n = 108

%

n= 223

%

n=111

%

n=216

%

Cardiac Disorders

Palpitations 0 0 2 0

Ear and Labyrinth Disorders

Vertigo 1 1 6 1

Eye Disorders

Diplopia 6 7 15 2

Vision Blurred 2 2 4 0

Gastrointestinal Disorders

Nausea 6 6 9 3

Constipation 2 4 8 0

Diarrhea 1 3 5 0

Vomiting 2 4 5 0

Dry Mouth 1 1 3 0

Abdominal Pain 2 2 1 0

Dyspepsia 2 2 0 0

Infections and Infestations

Nasopharyngitis 2 4 5 3

Pharyngitis 1 2 0 0

Urinary Tract Infection 2 5 0 2

Injury, Poisoning and Procedural

Complications

Head Injury 1 0 2 0

Investigations

Alanine Aminotransferase

Increased* 1 1 4 0

Aspartate Aminotransferase

Increased 1 1 3 0

Weight Decreased 2 0 1 0

Metabolism and Nutrition

Disorders

Decreased Appetite 3 1 5 1

Musculoskeletal and Connective

Tissue Disorders

Back Pain 4 2 5 3

Musculoskeletal Chest Pain 2 1 0 0

Nervous System Disorders

Somnolence 19 22 37 11

Dizziness 18 22 33 15

Fatigue 12 14 24 7

Headache 10 12 10 9

Balance Disorder 3 5 9 1

Gait Disturbance 1 3 8 1

Dysarthria 2 1 7 0

Nystagmus 3 7 6 0

Ataxia 2 3 6 2

Aphasia 2 1 4 0

Asthenia 0 1 3 1

Dysgeusia 2 0 2 0

Memory Impairment 2 1 2 0

Migraine 0 0 2 0

Sedation 1 1 2 0

Tremor 0 3 1 1

Psychiatric Disorders

Confusional State 2 2 3 0

Euphoric Mood 0 0 2 0

Irritability 1 0 2 0

Suicidal Ideation 2 1 0 0

Renal and Urinary Disorders

Pollakiuria 0 1 0 0

Reproductive System and Breast

Disorders

Dysmenorrhea 1 2 1 0

Respiratory, Thoracic and

Mediastinal Disorders

Hiccups 0 1 1 0

Dyspnea 0 3 0 0

Skin and Subcutaneous Tissue

Disorders

Pruritus 2 1 0 0

Rash Papular 2 0 0 0 * Reported as an adverse reaction; see Laboratory Abnormalities for ALT changes from collected laboratory values

Laboratory Abnormalities

Hepatic Transaminases

In Study 2, there was a post-baseline elevation of alanine aminotransferase (ALT) to greater than

3 times the upper limit of normal (ULN) in 1 (0.9%) patient treated with 100 mg XCOPRI, 2

(1.8%) patients treated with 200 mg, and 3 (2.7%) patients treated with 400 mg, compared to no

patients who took placebo. The maximum ALT elevation was 7.6 times ULN in patients treated

with 400 mg XCOPRI.

Potassium

In clinical studies, there was a post-baseline elevation of potassium values greater than 5 meq/L

(upper reference range) in patients treated with XCOPRI. In Study 1, there were 17 (17%) patients

treated with XCOPRI 200 mg compared to 8 (7%) patients who took placebo with normal baseline

potassium values who had at least one post-baseline maximum value greater than 5 meq/L. In

Study 2, there was a dose-related distribution where at least one post-baseline potassium value was

greater than 5 meq/L, occurring in 8.3%, 9.1%, and 10.8% of the patients treated with XCOPRI

100 mg, 200 mg, and 400 mg, respectively, compared to 5.6% of patients who took placebo. Two

patients had a maximum potassium value of 5.9 meq/L.

Other Adverse Reactions

Gastrointestinal disorders: There was an incidence of appendicitis in the overall clinical trial safety

population of 2.9 cases of appendicitis/1000 patient-years of exposure that is in excess of the

expected background rate in the general population.

Adverse Reactions Based on Gender

No significant gender differences were noted in the incidence of adverse reactions.

7 DRUG INTERACTIONS

7.1 Effect of XCOPRI on Other Drugs

Table 5 summarizes the effect of XCOPRI on other drugs [see Clinical Pharmacology (12.3)].

Table 5: Pharmacokinetic Drug Interactions

Drug or Substrate Type Effect of XCOPRI on Drug

or Substrate

Clinical Recommendation

Antiepileptic Drugs

lamotrigine plasma concentrations Because of a potential for

reduced efficacy of these

drugs, increase the dosage of

lamotrigine or

carbamazepine, as needed,

when used concomitantly

with XCOPRI.

carbamazepine plasma concentrations

phenytoin plasma concentrations Because of a potential 2-fold

increase in phenytoin levels,

gradually decrease phenytoin

dosage by up to 50% as

XCOPRI is being titrated.

phenobarbital plasma concentrations Because of a potential for an

increase in the risk of adverse

reactions from these drugs,

desmethylclobazam, the

active metabolite of clobazam

plasma concentrations

Drug or Substrate Type Effect of XCOPRI on Drug

or Substrate

Clinical Recommendation

consider a reduction in

dosage of phenobarbital or

clobazam, as clinically

appropriate, when used

concomitantly with XCOPRI.

CYP2B6 Substrates

plasma concentrations Because of a potential for

reduced efficacy of these

drugs, increase the dosage of

CYP2B6 or CYP3A4

substrates, as needed, when

used concomitantly with

XCOPRI.

CYP3A Substrates

plasma concentrations

Oral contraceptives plasma concentrations Because of the potential for

reduced efficacy of oral

contraceptives, women

should use additional or

alternative non-hormonal

birth control while taking

XCOPRI.

CYP2C19 Substrates plasma concentrations Because of a potential for an

increase in the risk of adverse

reactions from these drugs,

consider a reduction in

dosage of CYP2C19

substrates, as clinically

appropriate, when used

concomitantly with XCOPRI.

7.2 Drug that Shorten the QT Interval

XCOPRI can shorten the QT interval; therefore, caution should be used when administering

XCOPRI and other drugs that shorten the QT interval [see Warnings and Precautions (5.2) and

Clinical Pharmacology (12.2)].

7.3 CNS Depressants and Alcohol

Concomitant use of XCOPRI with other CNS depressants, including alcohol, may increase the risk

of neurological adverse reactions, including sedation and somnolence [see Warnings and

Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to

antiepileptic drugs (AEDs), such as XCOPRI, during pregnancy. Encourage women who are

taking XCOPRI during pregnancy to enroll in the North American Antiepileptic Drug (NAAED)

Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting

http://www.aedpregnancyregistry.org/.

Risk Summary

There are no adequate data on the developmental risk associated with the use of XCOPRI in

pregnant women.

In animal studies, administration of cenobamate during pregnancy or throughout pregnancy and

lactation resulted in adverse effects on development (increased embryofetal mortality, decreased

fetal and offspring body weights, neurobehavioral and reproductive impairment in offspring) at

clinically relevant drug exposures [see Data].

In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The

background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of cenobamate (0, 10, 30, or 60 mg/kg/day) to pregnant rats during the period

of organogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and

incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal

toxicity. There was a small increase in visceral malformations at the high dose; however,

teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths,

which resulted in an inadequate number of fetuses examined. Maternal plasma exposure (AUC) at

the no-effect dose for adverse effects on embryofetal development (30 mg/kg/day) was less than

that in humans at the maximum recommended human dose (MRHD) of 400 mg.

Oral administration of cenobamate (0, 4, 12, or 36 mg/kg/day) to pregnant rabbits during the period

of organogenesis resulted in increased embryofetal mortality at the highest dose tested, which was

associated with maternal toxicity. Maternal plasma exposure at the no-effect dose (12 mg/kg/day)

for adverse effects on embryofetal development was less than that in humans at the MRHD.

When cenobamate (0, 11, 22, or 44 mg/kg/day) was orally administered to female rats throughout

pregnancy and lactation, neurobehavioral impairment (learning and memory deficit and increased

auditory startle response) was observed in the offspring at all doses and decreased preweaning

body weight gain and adverse effects on reproductive function (decreased numbers of corpora

lutea, implantations, and live fetuses) were seen in the offspring at the high dose. Maternal plasma

exposure at the lowest effect dose (11 mg/kg/day) for adverse effects on pre- and postnatal

development was less than that in humans at the MRHD.

8.2 Lactation

Risk Summary

There are no data available on the presence of cenobamate in human milk, the effects on the

breastfed infant, or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the

mother’s clinical need for XCOPRI and any potential adverse effects on the breastfed infant from

XCOPRI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Women of reproductive potential concomitantly using oral contraceptives should use additional or

alternative non-hormonal birth control [see Drug Interactions (7.1) and Clinical Pharmacology

(12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Juvenile Animal Toxicity Data

Cenobamate was administered orally to juvenile rats from postnatal day (PND) 7 to 70. To

maintain consistent plasma drug exposures, doses were increased during the dosing period, up to

120 and 80 mg/kg/day in males and females, respectively. Adverse effects included mortality,

delayed sexual maturation, neurological (decreased grip strength) and neurobehavioral (learning

and memory deficits) impairment, decreased sperm count, decreased brain weight, and ocular

histopathology. Recovery from these effects was observed following discontinuation of dosing.

Overall, a no-effect dose for adverse effects on postnatal development was not identified. At the

lowest doses tested, plasma cenobamate exposures (AUC) were less than that in humans at the

maximum recommended human dose (MRHD) of 400 mg.

8.5 Geriatric Use

Clinical studies of XCOPRI did not include sufficient numbers of patients aged 65 and over to

determine the safety and efficacy of XCOPRI in the elderly population. In general, dose selection

for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting

the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or

other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

XCOPRI should be used with caution and dosage reduction may be considered in patients with

mild to moderate (CLcr 30 to less than 90 mL/min) and severe (CLcr less than 30 mL/min) renal

impairment. Use in patients with end-stage renal disease undergoing dialysis is not recommended

[see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

XCOPRI should be used with caution and in patients with mild to moderate (5-9 points on Child-

Pugh assessment; Class A or B) hepatic impairment. In these patients, the maximum recommended

dosage is 200 mg once daily and additional dosage reduction may be considered [see Dosage and

Administration (2.3) and Clinical Pharmacology (12.3)]. Use of XCOPRI in patients with severe

hepatic impairment is not recommended.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

XCOPRI contains cenobamate, a schedule V controlled substance.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological

or physiological effects. In a human abuse potential study conducted in recreational sedative

abusers (n=39), single doses of XCOPRI (200 mg and 400 mg) were compared to placebo.

XCOPRI at single doses of 400 mg produced responses on positive subjective measures such as

“Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were

statistically greater than the responses produced on these measures by placebo. In this study,

euphoric mood occurred at greater extent with XCOPRI (400 mg) (8%) than with placebo (0%).

Phase 1 multiple ascending dose studies in healthy subjects showed rates of euphoria and feeling

drunk of about 3% and disturbance in attention of about 5% in subjects who received

supratherapeutic doses of cenobamate, but these adverse events were absent in the placebo group.

In Phase 2 and 3 studies in subjects with epilepsy, euphoric mood, confusional state, and sedation

occurred at low rates in subjects who received XCOPRI (0.5-2.5%).

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to

repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or

a significant dose reduction of a drug. Clinical studies in healthy subjects indicate that XCOPRI

may cause physical dependence and lead to a withdrawal syndrome characterized by insomnia,

decreased appetite, depressed mood, tremor, and amnesia. XCOPRI should be withdrawn

gradually [see Warnings and Precautions (5.5)].

10 OVERDOSAGE

There is limited clinical experience with XCOPRI overdose in humans.

There is no specific antidote for overdose with XCOPRI. In the event of overdose, standard

medical practice for the management of any overdose should be used. An adequate airway,

oxygenation and ventilation should be ensured; monitoring of cardiac rate and rhythm and vital

signs is recommended. A certified poison control center should be contacted for updated

information on the management of overdose with XCOPRI. There are no data on the removal of

XCOPRI using dialysis.

11 DESCRIPTION

The chemical name of XCOPRI (cenobamate) is [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl]

carbamate. Its molecular formula is C10H10ClN5O2 and its molecular weight is

267.67 g/mol. The chemical structure is:

XCOPRI is a white to off-white crystalline powder. It is very soluble in aqueous solutions (water

1.7 mg/mL) and has higher solubility in organic solvents like ethanol (209.4 mg/mL).

XCOPRI tablets are for oral administration and contain the following inactive ingredients:

colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose,

and sodium starch glycolate and film coating agents specified below:

12.5 mg tablets: Not applicable, since 12.5 mg tablets are uncoated.

25 mg and 100 mg tablets: FD&C Blue# 2/indigo carmine aluminum lake, iron oxide red, iron

oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium

dioxide.

50 mg tablets: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed,

talc, and titanium dioxide.

150 mg and 200 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl

alcohol-part hydrolyzed, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-

onset seizures is unknown. Cenobamate has been demonstrated to reduce repetitive neuronal firing

by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the

γ-aminobutyric acid (GABAA) ion channel.

N

Cl

O

N

NNH2N

O

12.2 Pharmacodynamics

Interactions with Alcohol

No clinically significant differences on objective attention, psychomotor performance, and

memory tests, in addition to other subjective CNS tests, were observed following concomitant use

of XCOPRI and ethanol (preparation of 40% ethanol in orange juice dosed at 0.7 g/kg for males

and 0.57 g/kg for females) in healthy subjects.

Cardiac Electrophysiology

In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF

interval has been observed with XCOPRI [see Warnings and Precautions (5.2)]. The mean ΔΔQTc

is -11 [-13, -8] msec for 200 mg once daily and -18 [-22, -15] msec for 500 mg once daily (1.25

times the maximum recommended dosage). A higher percentage of XCOPRI-treated subjects

(31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to

placebo (6-17%). Reductions of the QTc interval below 300 msec were not observed.

12.3 Pharmacokinetics

Cenobamate AUC increases in a greater than dose-proportional manner following single oral doses

from 5 to 750 mg (0.0125 to 1.88 times the maximum recommended dosage). Cenobamate Cmax

increases in a dose proportional manner. Steady-state plasma concentrations are attained after

approximately two weeks of once daily dosing.

The pharmacokinetics of cenobamate are similar when used as monotherapy or as adjunctive

therapy for the treatment of partial-onset seizures, except plasma cenobamate multiple-dose

exposure (Cmax, AUC) decreased with co-administration of phenytoin by 27-28%.

Absorption

At least 88% of XCOPRI is absorbed following oral administration, with median Tmax ranging

from 1 to 4 hours.

Effect of Food

No clinically significant differences in cenobamate pharmacokinetics were observed following

administration of a high-fat meal (800-1000 calories with 50% fat).

Distribution

The apparent volume of distribution (Vd/F) of cenobamate after oral administration of XCOPRI

is approximately 40-50 L. Plasma protein binding of cenobamate is 60% and independent of

concentration in vitro. Cenobamate primarily binds with human albumin protein.

Elimination

The apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is

approximately 0.45-0.63 L/hour over a dose range from 100 mg/day to 400 mg/day.

Metabolism

Cenobamate is extensively metabolized. The primary metabolic pathways are by glucuronidation

via UGT2B7 and to a lesser extent by UGT2B4, and by oxidation via CYP2E1, CYP2A6,

CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.

Following administration of radiolabeled cenobamate, unchanged cenobamate accounted for

greater than 98% of the total AUC of radioactivity in plasma. Unchanged cenobamate accounted

for 6.8% of the dose which was mainly excreted in the urine (6.4%).

Excretion

Following administration of radiolabeled cenobamate, a mean of 93.0% of the total radioactive

dose was recovered in urine (87.8%) and feces (5.2%). More than 50% of the radioactivity was

excreted within 72 hours of dosing.

Specific Populations

No clinically significant differences in the pharmacokinetics of cenobamate were observed based

on age based on data from subjects age 18 years to 77 years, sex, or race/ethnicity based on data

from subjects categorized as Asian, Black, Caucasian, Hispanic, or Other.

Patients with Renal Impairment

Cenobamate plasma AUC was 1.4 fold to 1.5 fold higher in subjects with mild (CLcr 60 to less

than 90 mL/min) and moderate (CLcr 30 to less than 60 mL/min) following a single oral 200 mg

dose of XCOPRI compared to healthy controls. In subjects with severe (CLcr less than 30 mL/min)

renal impairment, cenobamate plasma AUC did not change significantly compared to healthy

controls following single oral 100 mg dose of XCOPRI [see Use in Specific Populations (8.6)].

The effect of hemodialysis on cenobamate pharmacokinetics has not been studied.

Patients with Hepatic Impairment

Cenobamate plasma AUC was 2.1-fold and 2.3-fold higher in subjects with mild (5-6 points on

Child-Pugh assessment) and moderate (7-9 points on Child-Pugh assessment) hepatic impairment,

respectively, following a single oral 200 mg dose of XCOPRI compared to matched healthy

controls [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].The effect

of severe hepatic impairment on cenobamate pharmacokinetics has not been studied.

Drug Interaction Studies

Clinical Studies

Alcohol

No clinically significant pharmacokinetic differences were observed for either cenobamate or

alcohol when administered concomitantly.

AEDs

Multiple doses of concomitant XCOPRI 200 mg once daily increased phenytoin mean Cmax and

AUC by 70% and 84%, respectively, and phenobarbital mean Cmax and AUC by 34% and 37%,

respectively [see Drug Interactions (7.1)]. Multiple doses of concomitant XCOPRI 200 mg once

daily decreased carbamazepine mean Cmax and AUC each by 23% [see Drug Interactions (7.1].

No clinically significant differences in the pharmacokinetics of the following drugs were observed

when used concomitantly with cenobamate: valproic acid, levetiracetam or lacosamide.

Based on population PK analyses, during treatment within the 100-400 mg/day XCOPRI dose

range, lamotrigine concentrations are expected to decrease by 21-52% [see Drug Interactions

(7.1)]; and levetiracetam concentrations are expected to decrease by 4-13%, which is not expected

to be clinically significant.

In subjects treated with XCOPRI in Study 1 and Study 2, there was no clear relationship between

efficacy and concomitant oxcarbazepine use. As such, the efficacy data from Study 1 and Study 2

do not support the existence of a clinically relevant interaction perpetrated by XCOPRI against

oxcarbazepine.

CYP Substrates

Multiple doses of concomitant XCOPRI 200 mg once daily decreased total bupropion (CYP2B6

substrate) mean Cmax and AUC by 23% and 39%, respectively, and decreased midazolam (CYP3A

substrate) mean Cmax and AUC by 61% and 72%, respectively [see Drug Interactions (7.1)].

Multiple doses of concomitant XCOPRI 200 mg once daily increased the omeprazole (CYP2C19

substrate) mean Cmax and AUC by 83% and 107%, respectively [see Drug Interactions (7.1)]. No

clinically significant differences in the pharmacokinetics of warfarin (CYP2C9 substrate) were

observed when used concomitantly with cenobamate.

The effects of concomitant AEDs on cenobamate PK

Plasma cenobamate multiple-dose exposure (Cmax, AUC) decreased with co-administration of

phenytoin by 27-28%. However, repeated dosing of valproate, phenobarbital, and carbamazepine

did not have any significant impact on plasma cenobamate multiple-dose exposure.

In Vitro Studies

CYP Enzymes

Cenobamate inhibits CYP2B6, CYP2C19, and CYP3A, but cenobamate does not inhibit CYP1A2,

CYP2C8, CYP2C9, or CYP2D6.

Cenobamate induces CYP2B6, CYP2C8, and CYP3A4, but cenobamate does not induce CYP1A2,

CYP2C9, or CYP2C19.

Transporters Systems

Cenobamate was not a substrate of P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2-K,

and cenobamate did not inhibit P-gp, OAT1, OCT1, OCT2, OATP1B3, BSEP, OAT3, or

OATP1B1.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Oral administration of cenobamate (0, 5, 15, or 35 mg/kg/day) to Tg.rasH2 mice for up to 26 weeks

did not result in an increase in tumors. Oral administration of cenobamate (0, 4, 8, or 20 mg/kg/day)

to male and female rats for up to 87 or 90 weeks, respectively, did not result in an increase in

tumors. Plasma exposure at the highest dose tested in rats was less than that in humans at the

maximum recommended human dose (MRHD) of 400 mg/day.

Mutagenesis

Cenobamate was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat

bone marrow micronucleus) assays.

Impairment of Fertility

Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to male and female rats prior to

and throughout mating and continuing in females to Gestation Day 6 did not produce adverse

effects on fertility, general reproductive performance, or early embryonic development. Plasma

exposure (AUC) at the highest dose tested in rats was less than that in humans at the MRHD.

14 CLINICAL STUDIES

The efficacy of XCOPRI for the treatment of partial-onset seizures was established in two

multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and

Study 2). Patients enrolled in the studies had partial-onset seizures with or without secondary

generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-

week baseline period, patients were required to have at least 3 or 4 partial-onset seizures per 28

days on average with no seizure-free period exceeding 3 to 4 weeks. In these studies, patients had

a mean duration of epilepsy of approximately 24 years and median baseline seizure frequency of

8.5 seizures per 28 days. More than 80% of patients were taking 2 or more concomitant AEDs.

Study 1 (NCT01397968) compared doses of XCOPRI 200 mg/day with placebo. Study 2

(NCT01866111) compared doses of XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with

placebo. Both studies had an 8-week baseline period to establish a baseline seizure frequency,

following which patients were randomized to a treatment arm. Patients entered a treatment period

consisting of an initial titration phase (6 weeks), and a subsequent maintenance phase (6 weeks for

Study 1 and 12 weeks for Study 2). In Study 1, patients were started on a daily dose of 50 mg (a

higher starting dose than currently recommended) and subsequently increased by 50 mg/day every

two weeks, until the final daily target dose of 200 mg/day was achieved. In Study 2, patients were

started on a daily dose of 50 mg (a higher starting dose than currently recommended) and

subsequently increased by 50 mg/day every week (a faster titration than currently recommended)

until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in

patients randomized to 400 mg/day [see Dosage and Administration (2.2), Warnings and

Precautions (5.1), and Adverse Reactions (6.1)].

The primary efficacy outcome in Study 1 and Study 2 was the percent change from baseline in

seizure frequency per 28 days in the treatment period. Table 6 summarizes the results of the

primary endpoint for XCOPRI in each study.

Table 6: Percent Change from Baseline in Seizure Frequency per 28 Days in the

Treatment Period (Study 1 and Study 2)

N

Median Percent Change from

Baseline in Seizure Frequency

per 28 Days (%)*

p-value

(Compared to

Placebo)

Study 1

Placebo 108 -21.5 --

XCOPRI 200 mg/day 113 -55.6 < 0.0001**

Study 2

Placebo 106 -24.3 --

XCOPRI 100 mg/day 108 -36.3 0.006**

XCOPRI 200 mg/day 109 -55.2 < 0.001**

XCOPRI 400 mg/day 111 -55.3 < 0.001** * A negative percent change from baseline in seizure frequency indicates reduction in seizure

frequency from baseline.

** Statistically significant compared to placebo

Figure 1 and Figure 2 show the proportion of patients with different percent reductions during the

maintenance phase over baseline in Study 1 and Study 2, respectively. Patients in whom the seizure

frequency increased are shown in the left-most column as “worse.” Patients in whom the seizure

frequency decreased are shown in the remaining four categories.

Figure 1: Proportion of Patients Exhibiting Different Percent Reductions During the

Maintenance Phase over Baseline in Study 1

Figure 2: Proportion of Patients Exhibiting Different Percent Reductions During the

Maintenance Phase over Baseline in Study 2

In Study 2, 4 of 102 (4%) patients in the XCOPRI 100 mg/day group, 11 of 98 (11%) patients in

the XCOPRI 200 mg/day group, and 20 of 95 (21%) patients in the XCOPRI 400 mg/day group

and 1 of 102 (1%) of patients in the placebo group reported no partial seizures during the

maintenance phase.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied XCOPRI tablets are supplied in the following configurations:

Bottles; 30 count

Strength NDC

Number

Tablet Description (Color, Shape, Markings)

50 mg 71699-050-30 Film coated round yellow tablets with SK on one side and 50 on

the other side

100 mg 71699-100-30 Film coated round brown tablets with SK on one side and 100 on

the other side

150 mg 71699-150-30 Film coated round light orange tablets with SK on one side and

150 on the other side

200 mg 71699-200-30 Film coated modified oval light orange tablets with SK on one

side and 200 on the other side

Titration Blister Packs; 28-Day

Daily Dose NDC

Number

Supplied As

[strength(quantity)]

Tablet Description (Color, Shape,

Markings)

12.5 mg per day

for 14 days, then

25 mg per day for

14 days

71699-201-28

12.5 mg (14-count) Uncoated round white to off-white tablets

with SK on one side and 12 on the other

side

25 mg (14-count) Film coated round brown tablets with SK

on one side and 25 on the other side

50 mg per day for

14 days, then 100

mg per day for 14

days

71699-202-28

50 mg (14-count) Film coated round yellow tablets with SK

on one side and 50 on the other side

100 mg (14-count) Film coated round brown tablets with SK

on one side and 100 on the other side

150 mg per day for

14 days, then 200

mg per day for 14

days

71699-203-28

150 mg (14-count) Film coated round light orange tablets with

SK on one side and 150 on the other side

200 mg (14-count) Film coated modified oval light orange

tablets with SK on one side and 200 on the

other side

Maintenance Blister Packs; 28-Day

Daily Dose NDC

Number

Supplied As

[strength(quantity)]

Tablet Description (Color, Shape,

Markings)

250 mg per day 71699-104-56

100 mg (28-count) Film coated round brown tablets with SK

on one side and 100 on the other side

150 mg (28-count) Film coated round light orange tablets with

SK on one side and 150 on the other side

350 mg per day 71699-103-56

150 mg (28-count) Film coated round light orange tablets with

SK on one side and 150 on the other side

200 mg (28-count) Film coated modified oval light orange

tablets with SK on one side and 200 on the

other side

16.2 Storage and Handling

Store XCOPRI tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C

(59°F to 86°F) (See USP Controlled Room Temperature).

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

DRESS/Multi-organ Hypersensitivity

Instruct patients and caregivers that a fever or rash associated with signs of other organ system

involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be

reported to their healthcare provider immediately. XCOPRI should be discontinued immediately if

a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.1)].

QT Shortening

Instruct patients to inform their healthcare provider of all of the medications, over-the-counter

medications, and herbal supplements that they are taking. Instruct patients to notify their healthcare

provider if they have any symptoms of shortening of the QT interval, including prolonged heart

palpitations or a loss of consciousness [see Warnings and Precautions (5.2)].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs, including XCOPRI, may

increase the risk of suicidal thoughts and behavior, and advise patients to be alert for the emergence

or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal

thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families

to report behaviors of concern immediately to a healthcare provider [see Warnings and

Precautions (5.3)].

Neurological Adverse Reactions

Counsel patients that XCOPRI causes somnolence, fatigue, dizziness, and gait disturbance. These

adverse reactions, if observed, are more likely to occur early in treatment but can occur at any

time. Advise patients not to drive or operate machinery until they have gained sufficient experience

on XCOPRI to gauge whether it adversely affects their ability to drive or operate machinery and

that other CNS depressants or alcohol may have additive effects [see Warnings and Precautions

(5.4)].

Withdrawal of XCOPRI

Advise patients not to discontinue use of XCOPRI without consulting with their healthcare

provider. XCOPRI should normally be gradually withdrawn to reduce the potential for increased

seizure frequency and status epilepticus [see Warnings and Precautions (5.5)].

Contraceptives

Counsel females of reproductive potential that XCOPRI may decrease the efficacy of oral

contraceptives and advise them to use additional or alternative non-hormonal birth control [see

Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become

pregnant during XCOPRI therapy. Encourage patients to enroll in the North American

Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting

information about the safety of antiepileptic drugs during pregnancy [see Use in Specific

Populations (8.1)].

Dosing Instructions

Counsel patients that XCOPRI may be taken any time with or without food. Instruct patients that

XCOPRI tablets should be swallowed whole with liquid and not chewed or crushed [see Dosage

and Administration (2.1)].

Abuse and Dependence

Advise patients that XCOPRI is a federally controlled substance (CV) because it can be abused or

lead to dependence [see Drug Abuse and Dependence (9)]. Advise patients to keep their

medication in a safe place to prevent misuse and abuse.

Manufactured for:

SK Life Science, Inc.

Paramus, NJ 07652

Phone: 1-866-657-5574

© 2020 SK Life Science, Inc.

XCOPRI® is a registered trademark of SK Life Science, Inc. or its affiliates and protected by U.S. Patent

7,598,279

MEDICATION GUIDE XCOPRI® (ex-koh-pree)

(cenobamate) tablets, for oral use, CV

What is the most important information I should know about XCOPRI? XCOPRI can cause serious side effects, including: 1. Serious or life threatening allergic reactions which may affect organs and other parts of your body like the liver or

blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away and go to the nearest emergency room if you have any of the following:

• swelling of your face, eyes, lips, or tongue • painful sores in the mouth or around your eyes • trouble swallowing or breathing • yellowing of your skin or eyes • a skin rash • unusual bruising or bleeding • hives • severe fatigue or weakness • fever, swollen glands, or sore throat that does not go

away or comes and goes • severe muscle pain • frequent infections that do not go away

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking XCOPRI. 2. Like other antiepileptic drugs, XCOPRI may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry

you: • thoughts about suicide or dying • trouble sleeping (insomnia) • attempts to commit suicide • new or worse irritability • new or worse depression • acting aggressive, being angry, or violent • new or worse anxiety • acting on dangerous impulses • feeling agitated or restless • an extreme increase in activity and talking (mania) • panic attacks • other unusual changes in behavior or mood

• Suicidal thoughts or actions may be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 3. Do not stop taking XCOPRI without first talking to your healthcare provider. • Stopping XCOPRI suddenly can cause serious problems. • Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus). 4. XCOPRI is a federally controlled substance (CV) because it can be abused or lead to dependence. Keep XCOPRI in a safe place to prevent misuse and abuse. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Selling or giving away XCOPRI may harm others and is against the law.

What is XCOPRI? XCOPRI is a prescription medicine used to treat partial-onset seizures in adults. It is not known if XCOPRI is safe and effective in children. Do not take XCOPRI if you: • are allergic to cenobamate, any of the other ingredients in XCOPRI. See the end of this Medication Guide for a complete list of

ingredients in XCOPRI. • have a genetic problem (called familial short QT syndrome) that affects the electrical system of the heart.

Before taking XCOPRI, tell your healthcare provider about all your medical conditions, including if you: • have or had depression, mood problems or suicidal thoughts or actions. • have liver, kidney, or blood problems. • have had an allergic reaction to a medicine which caused a rash or affected internal organs, like the liver or blood cells. • use birth control medicine. XCOPRI may cause your birth control medicine to be less effective. Talk to your healthcare

provider about the best birth control method to use while taking XCOPRI. • are pregnant or plan to become pregnant. It is not known if XCOPRI will harm your unborn baby. Tell your healthcare provider

right away if you become pregnant while taking XCOPRI. You and your healthcare provider will decide if you should take XCOPRI while you are pregnant. o If you become pregnant while taking XCOPRI, talk to your healthcare provider about registering with the North American

Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334 or go to www.aedpregnancyregistry.org

• are breastfeeding or plan to breastfeed. It is not known if XCOPRI passes into breastmilk. Talk to your healthcare provider about the best way to feed your baby while taking XCOPRI.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XCOPRI may affect the way other medicines work, and other medicines may affect how XCOPRI works. Do not start a new medicine without first talking with your healthcare provider. Ask your healthcare provider or pharmacist for a list of medicines you are taking, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take XCOPRI? • Take XCOPRI exactly as your healthcare provider tells you to take it. • It is very important to increase your dose of XCOPRI slowly, as instructed by your healthcare provider. • Do not stop taking XCOPRI without talking to your healthcare provider. Stopping XCOPRI suddenly can cause serious

problems, including seizures that will not stop (status epilepticus). • Your healthcare provider may change your dose, if needed. • Your healthcare provider will tell you how much XCOPRI to take. • XCOPRI can be taken at any time of day, with or without food. • Swallow tablets whole with liquid. Do not crush or chew. • Talk with your healthcare provider about what you should do if you miss a dose. • If you take too much XCOPRI, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking XCOPRI? • Do not drive, operate machinery or do other dangerous activities until you know how XCOPRI affects you. XCOPRI may slow

your thinking and motor skills and may affect your vision. • Do not drink alcohol or take other medicines that can make you sleepy or dizzy while taking XCOPRI without first talking to

your healthcare provider. What are the possible side effects of XCOPRI? XCOPRI may cause serious side effects, including: • See “What is the most important information I should know about XCOPRI?” • problems with the electrical system of the heart (QT shortening). Call your healthcare provider if you have symptoms of

QT shortening including fast heartbeat (heart palpitations) that last a long time or fainting. • nervous system problems. XCOPRI may cause problems that can affect your nervous system. Symptoms of nervous system

problems include: o dizziness o trouble walking or with coordination o feeling sleepy and tired o trouble concentrating, remembering, and thinking clearly o vision problems

The most common side effects of XCOPRI include: o feeling sleepy and tired o dizziness o double vision o headache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of XCOPRI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store XCOPRI? • Store XCOPRI at room temperature between 68°F to 77°F (20°C to 25°C). • Safely throw away medicine that is out of date or no longer needed. • Keep XCOPRI and all medicines out of the reach of children. General information about the safe and effective use of XCOPRI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XCOPRI for a condition for which it was not prescribed. Do not give XCOPRI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about XCOPRI that is written for health professionals.

What are the ingredients in XCOPRI? Active ingredient: cenobamate Inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. 25 mg and 100 mg tablets: FD&C Blue #2/indigo carmine aluminum lake, iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 50 mg tablets: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 150 mg and 200 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. Manufactured for SK Life Science, Inc., Paramus, NJ 07652 © 2019 SK Life Science, Inc. XCOPRI® is a registered trademark of SK Life Science, Inc. or its affiliates and protected by U.S. Patent 7,598,279 For more information, go to www.XCOPRI.com or call 1-866-657-5574.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2020